Accumulating evidence suggests that competitive demands regulate hemopoietic differentiation. Physiologic requirements for at least three blood cell groups, according to current thinking, are met through the action of three specific inducers: erythropoietin, granulopoietin (CSF?), and thrombopoietin. These are thought to act on unipotent stem cells, derived from pluripotent stem cells, committed to a specific line of differentiation and sensitive to the appropriate inducer. According to this scheme, availability of stem cells committed to one path of differentiation is determined by the relative demands on the pluripotent stem cell population for stem cells committed to the other pathways. Alternatively specific inducers may act on the pluripotent stem cell itself to regulate differentiation. We propose investigating whether in fact there are four (or more) stem cell populations (one pluripotent and three committed) or whether the pluripotent stem cell is the common target cell for inducers. If the action of an inducer is restricted to the appropriate unipotent stem cell, the presence of another inducer should not alter the response to it. Our approach to this problem is: (1) To determine the effect of CSF on erythropoietin-stimulated iron uptake, hemoglobin synthesis and erythroid colony formation by marrow cells in vitro. Preliminary evidence has shown that CSF inhibits iron uptake and hemoglobin synthesis by rat marrow cells stimulated with erythropoietin. (2) To determine the effect of erythropoietin on myeloid colony formation in vitro. (3) To determine whether erythropoietin and CSF have an effect on the maintenance of pluripotent stem cells in primary marrow explants. (4) To make use of marrow from genetically anemic mice lacking normal numbers of pluripotent stem cells in (1), (2), and (3) above. (5) To extend efforts on marrow cell fractionation with the aim of isolating pluripotent stem cells and determinig their sensitivity to erythropoietin and CSF. (6) To explore the effects of putative thrombopoietin preparations on both CSF and erythropoietin action.